Cancer refers to more than one hundred clinically distinct forms of disease. Almost every tissue of the body can give rise to cancer and some can even yield several types of cancer. Cancer is characterized by an abnormal growth of cells that can invade the tissue of origin or spread to other sites. In fact, the seriousness of a particular cancer, or its degree of malignancy, is based upon the propensity of cancer cells to invade neighboring tissue and to spread. That is, various human cancers (e.g., carcinomas) differ appreciably as to their ability to spread from a primary site or tumor, and to metastasize throughout the body. Indeed, it is the process of tumor metastasis that is detrimental to long-term survival of the cancer patient. A surgeon can remove a primary tumor, but a cancer that has metastasized often reaches too many places to permit a surgical cure. To successfully metastasize, cancer cells must detach from their original location, invade into a blood or lymphatic vessel, travel in the circulation to a new site, and establish a tumor there.
The twelve major cancers are prostate, breast, lung, colorectal, bladder, non-Hodgkin's lymphoma, uterine, melanoma, kidney, leukemia, ovarian, and pancreatic cancers. Melanoma is a major cancer and a growing worldwide health problem by virtue of its ability to metastasize to most organs in the body which include lymph nodes, lungs, liver, brain, and bone. The clinical outcome for patients with metastasis to distant sites is significantly worse than that seen with regional lymph node metastases. The median survival time for patients with lung metastases is eleven months while that for patients with liver, brain, and bone metastases is four months. Four types of treatment have been used for distant melanoma metastases: surgery, radiation therapy, chemotherapy, and immunotherapy. Surgery is most often used to improve the quality of life of the patient, such as removing a metastasis that is obstructing the gastrointestinal tract. Radiation therapy has some degree of efficacy in local control of metastases, but is primarily limited to cutaneous and/or lymph node metastases. A number of chemotherapeutic agents have been evaluated for the treatment of metastatic melanoma. However, only two cytotoxic drugs are able to achieve a response rate of 10% or more. These drugs are decarbazine (DTIC) and nitrosoureas. Only DTIC is approved for the treatment of melanoma in most countries. Subsequently, the lack of clinically significant, beneficial, long-term effects of surgery, radiation therapy, and chemotherapy for the treatment of metastatic melanoma has led to the use of immunotherapy. Thus far, most attention has been given to the cytokines interleukin-2 and interferon-α. Clinical trials have yielded better results with interleukin-2 but, on average, only 15% of patients with metastatic melanoma exhibit a significant reduction in tumor burden in response to interleukin-2.
Similar to melanoma, other cancers become seriously life threatening once metastasis occurs. Pancreatic cancer yields a 3% chance of survival beyond one year after metastasis (e.g., first diagnosis) occurs. This increases only to 18% upon treatment with the cytotoxic drug gemcitabine and 24% upon treatment with gemcitabine, tarceva, and the EGFr kinase inhibitor. Prostate cancer can be successfully controlled by surgery or radiation as long as the cancer is confined to the prostate. But there is little effective treatment available once metastasis occurs, especially if androgen-deprivation therapy fails.
Other cancers may be more effectively treated with chemotherapeutic agents than melanoma, pancreatic, or prostate cancer. Chemotherapeutic agents, however, suffer two major limitations. First, the chemotherapeutic agents are not specific to cancer cells and particularly at high doses, they are toxic to normal rapidly dividing cells. Second, with time cancer cells develop resistance to chemotherapeutic agents thereby providing no further benefit to the patient. As noted for melanoma, other treatment modalities have been explored to address the limitations arising from the use of chemotherapeutic agents. Nonetheless, these additional treatments have been of limited success for the treatment of other cancers. Examples of additional cancer treatments and their limitations include surgery (inability to completely remove extensive metastasis), radiation (inability to selectively deliver radiation to cancer cells), and immunotherapy (the use of toxic cytokines with limited efficacy). For this reason, other newer therapeutic approaches are under exploration (e.g., antiangiogenesis agents, apoptosis agents, gene therapy) but these treatments are, relatively speaking, in their infancy. Therefore, a need still exists for novel approaches exemplified by novel chemotherapeutic agents which are efficacious (e.g., reduction in tumor size or spread of metastases), have limited toxicity for the treatment of cancer, prolong the time to develop drug resistance, or any combination thereof.